The Role of Donor Innate Immune Responses in Regulating Alloimmunity after Heart Transplantation

供体先天免疫反应在心脏移植后调节同种免疫中的作用

基本信息

批准号：
10405512
负责人：
Daniel Kreisel
金额：
$ 63.66万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405512
关键词：
Ablation Admixture Adverse effects Allograft Tolerance Allografting Apoptosis Applications Grants Automobile Driving Blood Circulation Cardiac Cardiac Myocytes Cell Death Cell model Cells Clinical Collaborations Cues Cytokine Signaling Development Endothelial Cells Event Foundations Goals Graft Enhancements Graft Rejection Graft Survival Heart Heart Transplantation Heart failure Heterogeneity Human Immune Immune Targeting Immune response Immunologics Infection Inflammation Inflammatory Inflammatory Response Innate Immune Response Interferon Type I Intervention Leukocyte Trafficking Leukocytes Life Link Mediating Medicine Molecular Mouse Strains Mus Nature Neutrophil Infiltration Organ Organ Transplantation Outcome Pathogenesis Pathway interactions Patients Pattern Phase Plasma Cells Play Population Process Production Publications Regimen Reperfusion Injury Reperfusion Therapy Reporting Research Research Personnel Role Shapes Signal Transduction Solid Surface TLR4 gene Techniques Testing Time Tissues Transplant Recipients Transplantation Work allograft rejection base experimental study graft dysfunction high risk improved improved outcome innate immune pathways insight intravital microscopy isoimmunity macrophage monocyte novel novel therapeutics prevent recruit response side effect single-cell RNA sequencing success treatment choice treatment strategy

项目摘要

PROJECT SUMMARY/ABSTRACT The success of heart transplantation is limited by ischemia reperfusion injury-mediated primary graft dysfunction and allograft rejection, two processes that may be immunologically linked. Current strategies to reduce graft rejection and improve survival are mostly based on ablation of recipient immune cell populations. These approaches are only modestly effective and carry high risks of life-threatening infections. An alternative and potentially safer approach is to target immune pathways and cell populations within the donor graft that initiate inflammatory responses and resultant alloreactivity. The ability to precisely control the initial immune response following heart transplantation represents a promising approach to increase allograft tolerance and improve clinical outcomes. Our recent work has identified that ferroptosis, a non-apoptotic form of inflammatory cell death mediates the early inflammatory response after reperfusion of heart grafts. We have discovered that graft endothelial cells and tissue-resident CCR2+ macrophages play important and complementary roles in promoting the recruitment of inflammatory immune cells to the transplanted heart. In this proposal, we will use state-of-the- art techniques, including intravital microscopy, single cell RNA sequencing and novel mouse strains to perform studies that will 1) define mechanisms of cell death (Aim1), 2) evaluate the role of cell-specific inflammatory cytokine signaling (Aim 2) and 3) examine the role of cardiac macrophage heterogeneity (Aim 3) in driving innate inflammatory and alloimmune responses after heart transplantation. Our studies will lay the foundation for novel therapy that will improve outcomes after cardiac transplantation.

项目概要/摘要心脏移植的成功受到缺血再灌注损伤介导的原发性移植物功能障碍的限制和同种异体移植排斥，这两个过程可能与免疫学相关。当前减少腐败的策略排斥反应和提高生存率主要基于受体免疫细胞群的消融。这些方法的效果有限，并且存在危及生命的感染的高风险。替代方案和可能更安全的方法是针对供体移植物内的免疫途径和细胞群，从而启动炎症反应和由此产生的同种异体反应性。精确控制初始免疫反应的能力心脏移植后是一种有前途的方法，可以增加同种异体移植物的耐受性并改善临床结果。我们最近的工作发现铁死亡是炎症细胞死亡的一种非凋亡形式介导心脏移植物再灌注后的早期炎症反应。我们发现移植内皮细胞和组织驻留的 CCR2+ 巨噬细胞在促进将炎症免疫细胞募集到移植心脏。在本提案中，我们将使用最先进的艺术技术，包括活体显微镜、单细胞 RNA 测序和新的小鼠品系来执行研究将 1) 定义细胞死亡机制 (Aim1)，2) 评估细胞特异性炎症的作用细胞因子信号传导（目标 2）和 3）检查心脏巨噬细胞异质性（目标 3）在驱动先天性中的作用心脏移植后的炎症和同种免疫反应。我们的学习将为小说奠定基础治疗将改善心脏移植后的结果。